Susceptibility to infectious disease is one of the most strongly inherited of all common disease traits. Yet, we still do not have a clear understanding of how host genetic regulation of the immune response ultimately affects disease outcome. Slam genes comprise a family of tightly linked genes that encode costimulatory/adhesion molecules that transduce signals through association with the cytosolic adapter protein, SLAM-associated protein (SAP). Mutations in the gene encoding SAP (Sh2d1a) results in the development of a serious immunodeficiency that often results in mortality due to to virus infection, highlighting th central role that the Slam/SAP signaling pathway plays in the host response to viral pathogens. Slam genes are polymorphic in humans and in mice, and these polymorphisms have been linked to the development of autoimmunity. However, despite the significant role that the Slam/SAP signaling pathway plays in the host response to virus infection, there has been almost no study of the potential contribution of Slam locus polymorphisms to susceptibility to virus infection. We addressed this question utilizing a congenic mouse strain in which Slam alleles from one strain of mouse (129X1/SvJ) were introgressed onto the genetic background of another (B6) and asked whether natural genetic variation at this locus regulates susceptibility to viral infection. Published data using indicates that this congenic interval regulates susceptibilty to Coxsackievirus B3-induced myocarditis. New preliminary data suggest that this congenic interval also regulates susceptibility to influenza A. B6.129 congenic mice experienced a dramatic increase in mortality after H1N1 influenza infection compared to B6 mice. Susceptibility was associated with a significant increase in lung ?? T cells soon after infection. Further examination revealed that a significantly higher fraction of the lung ?? T cells in the susceptble B6.129 mice were producing IL-17A, a cytokine that has been shown to promote immunopathology after influenza infection. Taken together, these published and preliminary data suggest that we have identified a genetic locus that regulates susceptibility to two different viral infections and that the common feature appears to be alterations in the number and function of ?? T cells. Our overall hypothesis is that genetic variation at one or more Slam genes within the congenic interval regulates susceptibility to virus infection through regulation o ?? T cell function. To test this hypothesis, we will (1) determine the mechanisms through which the congenic interval regulates lung ?? T cell expansion and function after influenza infection and (2) identify the gene(s) within the congenic interval that regulates susceptibility to influenz and ?? T cell number and function. Upon completion of these Aims, we will have identified a candidate host gene(s) that regulates susceptibility to primary infection by a pathogenic H1N1 influenza strain, and that regulates the increase in potentially pathogenic IL-17-producing ?? cells in the lung after a respiratory infection that exerts a significant burden on public health.